Tamm-Horsfali protein(THP) is urine's most abundant protein. Its function has remained unclear, despite extensive research for over a century. One of the hypotheses about its function has been that it acts as a host defense actor against urinary tract infection. We are one of two groups to create the first gene knockout mouse for THP. [unreadable] [unreadable] In PRELIMINARY STUDIES, THP-deficient mice have difficulty clearing bacteria from the urinary bladder. [unreadable] [unreadable] The SPECIFIC AIMS of this proposal are: [unreadable] [unreadable] AIM#1) To define and circumscribe the role of THP as a host defense factor against UTI a) To determine if THP (-/-) mice are more prone to cystitis (inflammation of urinary bladder) in comparison with THP (+/+) mice, after transurethral inoculation of E.coli. b) To determine if THP (-/-) mice are more prone to pyelonephritis (inflammation of kidneys) in comparison with THP (+/+) mice, after transurethral inoculation of E.coli. c) To determine if the severity of bladder and kidney infection in THP (-/-) mice is related to the specific type of fimbrial expression in E. coll. d) To determine if THP (-/-) mice are more prone to UTI with bacteria other than E co//r specifically Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus saprophyticus, Enterococcus fecaelis and Morganella morganii, as measured by bladder and kidney bacterial loads after transurethral inoculation. [unreadable] [unreadable] AIM#2) To determine the mechanism of THP affecting the susceptibility for UTI a) Effect of THP on bacterial clearance from bladder . b) Effect of THP on bacterial - urothelial cell interaction c) Effect of THP on bacterial-leukocyte interaction [unreadable] [unreadable] Significance: These studies will clarify the function of urine's most abundant protein and will provide new knowledge about a host defense mechanism against UTI. The findings will allow a better understanding of the pathogenesis of UTI, a common human illness. [unreadable] [unreadable]